UC Riverside

Macrocyclic peptides are proven binders against structureless proteins. The complexity incorporated in multiple cyclization within a peptide backbone demands demonstration in multifaceted binding activity. We introduce the applications of cyclic peptide and an outline of the various research projects we aim to develop around them. As a starting point, we demonstrate the scope of our bicyclic peptides as highly specific fluorescent reporter probes for MAPK/ERK signaling pathway, often aberrantly involved in cancer. Bicyclic peptides can be designed to be highly specific binders for homologous ERK1 and 2 and can signal its phosphorylation. A library of significant diversity can assist in discovering such probes. The transcription factor c-Myc is a proto-oncogene which is overexpressed in most known cancers. c-Myc is commonly considered “undruggable” due to its intrinsically disordered structure. We had previously discovered a bicyclic peptide that could effectively inhibit the proliferation of a c-Myc-dependent cell line. Its drawbacks as a therapeutic were addressed through a series of medicinal chemistry modifications. We also address cytotoxicity concerns, applicability across multiple cancer cell lines, and mechanistic details of suppressed proliferation through multiple optimization processes. Additionally, we explored the potential of peptides as miniature enzyme and the structural considerations necessary for designing such molecules.